The exact pathogenesis of an infection with Shiga toxin (Stx)- producing E. coli (STEC) resulting in hemolytic uremic syndrome (HUS) is only partially understood. During extensive hemolysis as in STEC-HUS, heme is released into the extracellular space. In the early stages of the disease, heme is directly scavenged by hemopexin and degraded by heme oxygenase 1 (HO-1) thereby preventing heme-mediated toxicity. However, during the progression to thrombotic microangiopathy (TMA), the scavengers are rapidly depleted, leading to accumulation of heme. In this study, we measured levels of extracellular heme, hemopexin, and HO-1 in a cohort of STEC-HUS patients. Furthermore, the effects of heme in combination with Stx2 on endothelium were assessed in vitro.

Material and methods:

Circulating heme levels were quantified by spectrophotometric assay in 48 pediatric STEC-HUS patients admitted in the acute phase to Radboudumc between 1990-2016. Plasma hemopexin and HO-1 levels were determined by a sandwich ELISA. Primary human glomerular microvascular endothelial cells were exposed to heme, Stx2, or a combination of both, and HO-1 activity was assessed.

Elevated heme levels were found in the acute phase in STEC-HUS patients. These heme levels activate endothelial cells, promote pro-thrombotic state and cause endothelial injury in vitro, which are all relevant events in the pathogenesis of HUS. Importantly, the Stx2-mediated failure to adequate scavenge heme by intracellular HO-1 likely exaggerates these events.